Age-related macular degeneration (AMD) is a leading cause of blindness worldwide. In the USA the prevalence of advanced AMD is approaching epidemic proportions. The long-term goal of the proposed research is the development of prognostic technology for use in clinical medicine to assess AMD risk for severe visual loss and to monitor the efficacy of AMD therapeutics. We have quantified plasma CEP (carboxyethylpyrrole) biomarkers and genotyped four AMD risk polymorphisms in over 1400 AMD and control subjects. The AMD risk for those exhibiting elevated CEP markers and AMD risk genotypes was 2-3 fold greater than the risk based on genotype alone. Preliminary published results from a relatively small study population suggest that plasma protein carboxymethyllysine (CML) and pentosidine exhibit AMD biomarker potential. Namely, CML and CEP adducts discriminate between AMD and control subjects with about equal accuracy (~78%), pentosidine with ~88% accuracy, and CEP plus pentosidine with ~92% accuracy. Unpublished preliminary results also indicate that CEP biomarkers have potential utility in monitoring select AMD therapeutics and that CML and pentosidine offer promise in assessing the risk of progression to advanced dry AMD. We hypothesize that plasma protein CEP, CML and pentosidine in combination with genomic markers will provide clinically useful prognostic tests for assessing the risk of severe visual loss due to AMD and for monitoring AMD therapeutics. Two specific aims are proposed: (1) Validate plasma protein CML and pentosidine as AMD biomarkers in a larger study population in combination with genomic markers of AMD risk; and (2) Develop a LC MS/MS assay for plasma protein CEP adducts to enhance the accuracy, precision and utility of CEP measurements as predictors of AMD risk. Unique resources supporting the proposed research include our large repository of plasma from clinically documented, extensively characterized AMD and control donors, our state-of-the-art proteomic, mass spectrometric and genomic technologies, over a decade of experience in AMD biology and a world-class clinical ophthalmology and basic vision science research environment. )